REVITALISING CLINICAL RESEARCH IN SOUTH AFRICA 3
A STUDY ON CLINICAL RESEARCH AND RELATED TRAINING IN SOUTH AFRICA
From an epidemiological perspective, clinical research is seen as the application of the methods and techniques of epidemiology (a population science) to clinical decision-making. The main focus is thus on the fact that groups of patients or healthy people are studied in order to make health predictions about individuals. The term ‘clinical epidemiology’ has been coined to distinguish this research domain from classical epidemiology, which focuses on guiding decisions at the aggregate public health level. As shown in the box below, clinical researchers (also known as clinical epidemiologists) study a wide selection of issues that are pertinent to patient care.
The classification of clinical research provided by Grimes and Schultz (2002) offers further insight into the epidemiological paradigm (see Figure 1.1). In this approach, clinical research can be divided into experimental and observational studies, depending on whether or not the investigator allocates the exposure (treatment). Experimental studies are further subdivided into randomised and non-randomised trials, and observational studies into analytical or descriptive categories. Analytical studies incorporate a comparison (control) group, whereas descriptive studies do not. Furthermore, within analytical studies, cohort studies follow people forward from exposure to outcome, contrasting with case-control studies in which individuals are traced backwards from outcome to exposure. cross-sectional studies in turn are snapshots of exposures and outcomes within a group at one instant in time. Finally, descriptive studies such as case series lack a comparison group and therefore cannot examine associations, although they can be important for generating hypotheses.
RESEaRch iNtEREStS OF cliNical EpidEMiOlOgiStS (Fletcher and Fletcher, 2005) abnormality Is this patient sick or well?
diagnosis How accurate is this test?
Frequency How often does this disease occur?
Risk What factors increase the risk of this disease?
prognosis What are the consequences of this disease?
treatment Does treatment change the course of this disease?
prevention Does early intervention keep this disease from occurring?
cause What conditions lead to the disease?
Clinical researchers are able to choose from any of the above study designs.
As each design offers specific strengths and limitations, the choice should be determined by the research question being examined.
A second, considerably narrower perspective on clinical research is encountered in the biopharmaceutical industry where clinical research is seen as part of the drug development process, comprising distinct preclinical and clinical phases.
Preclinical research involves laboratory screening for promising chemical compounds, as well as research on laboratory animals to assess the toxicity and biological activity of these entities. A small percentage of the compounds so tested proceed to the stage of clinical research, with four phases of human experimentation. phase i trials concentrate on dose determination, safety and pharmacokinetics, and typically involve small numbers (<100) of human volunteers. phase ii trials are also small-scale, and are often placebo-controlled studies of efficacy and safety conducted among patients suffering from a particular target disease. phase iii trials are fully powered in the statistical sense, and are usually randomised studies in which the efficacy of a new drug is assessed in relation to placebo or another active drug as comparator. Finally, phase iV trials consist of post-marketing surveillance studies that can provide useful information on drug adverse effects, but are not infrequently initiated with the purpose of bringing the new drug to the attention of a large number of clinicians, often on a geographic or regional basis.
I N T R O D U C T I O N : C L I N I C A L R E S E A R C H I S T H E k E Y T O B E T T E R H E A LT H C A R E
REVITALISING CLINICAL RESEARCH IN SOUTH AFRICA 5
A STUDY ON CLINICAL RESEARCH AND RELATED TRAINING IN SOUTH AFRICA
Figure 1.1: Algorithm for classification of types of clinical research translational science is the third lens though which clinical research may be viewed. The establishment and growth of laboratory-based biomedical science from the 20th century onwards contributed greatly to a better understanding of human biology and disease mechanisms, and this in turn has led to many important medical breakthroughs, such as the discovery of antibiotics, cures for many nutritional disorders, eradication of smallpox and treatments for diabetes and HIV/AIDS. Concern has, however, often been expressed about the fact that many basic science discoveries have not (yet) resulted in direct benefits to patients. Organisations such as the US National Institutes of Health (NIH) have strongly promoted and supported ‘translational research’ in order to bridge this gap between basic science and clinical application.
The pathway of discovery within a translational science paradigm typically begins at ‘the bench’ where scientists study the mechanisms of disease at a molecular or cellular level, with subsequent progress to the clinical level (‘the bedside’) where studies are conducted to determine whether findings in animal models apply to human disease states. Proof-of-concept evidence has to be generated prior to potential therapies being tested in clinical trials. Much
Did investigator assign exposures?
Experimental study Observational study
Random allocation? Comparison group?
Randomised controlled
trail
randomised Non controlled
trail
Analytical
study Descriptive study Direction?
Cohort study
Case control
study
Cross sectional
study
Yes No
No No Yes
Yes
Exposure Outcome Exposure Outcome
Exposure and outcome at
the same time
of this research tends to emphasise ‘mechanistic studies’ aimed at furthering the understanding of physiological or pathological processes in humans, rather than evaluating the effects of rational interventions. Understanding these underlying processes is nevertheless very important for accelerating the development of novel approaches to treatment, improving the safety profile of existing interventions and advancing new diagnostic methods.
It is well understood, however, that new discoveries are not always initiated at the bench. Observations by astute clinicians of variations in disease processes in different patients may generate important hypotheses for testing in the laboratory, which in turn can spur important new innovations. Translational research can thus be regarded as being a bi-directional (‘bench-to-bedside and back-to-the-bench’) process in which basic scientists and clinical researchers are engaged in a symbiotic relationship.
in summary, three main perspectives on clinical research are currently identifiable. For some, clinical research is the application of epidemiological methods in the search for valid answers to questions regarding diagnosis, prevention, therapy, prognosis, aetiology and other issues relevant to patient care. Others view clinical research as experimental research aimed at establishing the risks and benefits associated with new pharmaceutical products. A third group regards clinical research as a scientific activity directed at testing or generating hypotheses about disease mechanisms, with the ultimate aim of accelerating the translation of basic science discoveries to useful clinical applications. it is obvious that the three perspectives are mutually interdependent.